There has been a resurgence of interest in marijuana for medicinal purposes. Recent legislation allows medicinal marijuana smoking and laws exist permitting marijuana research in disease treatment. Smoking is a poor cannabinoid delivery mode for glaucoma treatment because of the required technique, the introduction of patients to smoking, and marijuana cigarettes produce more carcinogens than tobacco. Topical administration of an efficacious cannabinoid in a delivery vehicle that enhances ocular penetration would be desirable. Many new drug delivery systems have been developed since delta-9-tetrahydrocannabinol (THC) was tried topically in light mineral oil which, while reducing intraocular pressure (IOP) in rabbits, dogs, cats and monkeys, was ineffective in reducing human IOP due to ocular irritation difficulties. Light mineral oil gave better delivery of delta9-THC to albino rabbit eye fluids and tissues. We hypothesize that new delivery systems will greatly enhance the safety and efficacy of lipophilic cannabinoids in reducing IP in all species, including man. To achieve these goals we will: I) determine the penetration rate of 3H-delta9-THC, previously identified as active in reducing IOP, using new topical ocular delivery systems with the isolated rabbit cornea. We will measure both trans-corneal drug passage and the corneal epithelial and stromal/endothelial tissue content. At least ten vehicles will be tested to identify four that give most trans-corneal drug transfer. ii) determine 3H-delta9-THC pharmacokinetics in pigmented rabbits eyes in order to identify tissue distribution patterns, kinetics, area-under-the curve, and the two most effective in vivo, vehicle delivery systems. Four vehicles will be employed (from aim I). GC/MS will identify metabolites in eye tissues. Iii) measure IOP in the eyes of normotensive or ocular hypertensive pigmented rabbits using several active cannabinoids in order to determine their pharmacological activity when presented in the two best of the newly- defined delivery vehicles (from aim ii). Progression will occur from one cannabinoid and ten vehicles to two vehicles and all available cannabinoids. Those drug/vehicle combinations yielding the best and most consistent falls in IOP will be examined for their effects on aqueous humor dynamics.